The transcription factor NF-kB has been shown by our group and by others to be involved with oncogenesis and to provide protection against a variety of apoptotic stimuli. Thus, we have previously shown that inhibition of NF-KB blocks cellular transformation and tumorigenesis induced by oncoproteins. Furthermore we have shown that several chemotherapies activate NF-kB in tumor cells and that inhibition of NF-kB by expression of IkB alpha, the inhibitor of NF-kB, strongly enhances the cytotoxic effect of both chemotherapy and radiation via the induction of apoptosis. Based on these studies, we are examining whether the current regimen of breast cancer chemotherapies would be augmented in their efficacy through the inhibition of NF-kB. We propose to examine breast cancer cell lines, human xenograft tumors, and breast tumors generated in animal models as to whether we can obtain enhanced responses to the current regimen of breast cancer chemotherapies when NF-kB is inhibited within the tumor. Additionally, we are proposing to examine whether other chemotherapies (such as CPT-11) which have not been effective or not tested for breast cancer will show activity against breast cancer when NF-kB is inhibited as an adjuvant approach to the chemotherapy. We will also examine whether chemotherapy treatment of breast tumors activates the expression of NF-KB-regulated genes which are known to encode proteins which block apoptosis or which provide multidrug resistance. Our studies potentially will lead to new adjuvant approaches to breast cancer therapy and will lead to the identification of NF-KB-regulated genes which may serve as markers for chemoresistance and which may ultimately serve as targets themselves for therapies to enhance the responses of breast cancer to chemotherapy. Finally, we propose a clinical trial for breast cancer utilizing liposomal adriamycin (Doxil(R) in combination with PS-341, the FDA-approved proteasome inhibitor known to efficiently block NF-kB activation.